代谢酶和转运体的药物遗传学对健康志愿者替米沙坦药代动力学的影响。
The impact of pharmacogenetics of metabolic enzymes and transporters on the pharmacokinetics of telmisartan in healthy volunteers.
机构信息
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
出版信息
Pharmacogenet Genomics. 2011 Sep;21(9):523-30. doi: 10.1097/FPC.0b013e3283482502.
OBJECTIVE
Telmisartan is mainly taken up into the liver by organic anion transporting polypeptide (OATP) 1B3, conjugated with glucuronate, and excreted into the bile. We investigated the relationship between genotypes of metabolizing enzymes and transporters and pharmacokinetics of telmisartan in clinical study. We also checked which enzymes are responsible for telmisartan glucuronidation.
MATERIALS AND METHODS
We collected blood samples from 57 healthy volunteers who had participated in a clinical trial of telmisartan and examined the relationship between 14 mutations in six transporters/metabolic enzymes and pharmacokinetics of telmisartan. We also performed an in-vitro glucuronidation assay with recombinant uridine 5'-diphospho-glucuronosyltransferases isoforms and human liver microsomes.
RESULTS
In the clinical study, area under the plasma concentration-time curve value from time zero to infinity, of telmisartan in heterozygotes of SLCO1B3 (encoding protein: OATP1B3) rs11045585 tended to be larger than that in homozygotes of wild-type alleles. Unexpectedly, 19 heterozygotes of UGT1A128, whose function was decreased, significantly increased its oral clearance compared with homozygotes of UGT1A11 alleles (1090±690 vs. 620±430 ml/min/body). Metabolic clearance of telmisartan in human liver microsomes obtained from individuals with UGT1A1*28/28 was higher compared with that of UGT1A11/*1 (168±33 vs. 93.3±27.3 μl/min/mg protein). Although telmisartan was metabolized by multiple UGT isoforms, in-vitro experiments revealed that UGT1A3 was estimated to be predominantly involved in telmisartan glucuronidation in human hepatocytes.
CONCLUSION
UGT1A1*28 was thought to enhance the protein expression of UGT1A3 as reported most recently (Riedmaier et al. Clin Pharmacol Ther 2010; 87:65-73) and thereby increase glucuronidation activity of telmisartan and decrease the plasma concentration of telmisartan.
目的
替米沙坦主要通过有机阴离子转运多肽（OATP）1B3 摄取进入肝脏，与葡萄糖醛酸结合，并排泄到胆汁中。我们研究了代谢酶和转运体的基因型与替米沙坦药代动力学之间的关系。我们还检查了哪些酶负责替米沙坦的葡萄糖醛酸化。
材料和方法
我们收集了 57 名参加替米沙坦临床试验的健康志愿者的血样，并研究了 6 种转运体/代谢酶中的 14 种突变与替米沙坦药代动力学之间的关系。我们还用人肝微粒体和重组尿苷 5′-二磷酸葡萄糖醛酸基转移酶同工酶进行了体外葡萄糖醛酸化试验。
结果
在临床研究中，替米沙坦的血浆浓度-时间曲线下面积从 0 到无穷大（AUC0-∞），SLCO1B3（编码蛋白：OATP1B3）rs11045585 的杂合子倾向于大于野生型等位基因的纯合子。出乎意料的是，19 名 UGT1A128 杂合子（其功能降低）的口服清除率明显高于 UGT1A11 等位基因的纯合子（1090±690 比 620±430 ml/min/体）。从 UGT1A1*28/28 的个体获得的人肝微粒体中替米沙坦的代谢清除率高于 UGT1A11/*1（168±33 比 93.3±27.3 μl/min/mg 蛋白）。尽管替米沙坦被多种 UGT 同工酶代谢，但体外实验表明 UGT1A3 估计是人类肝细胞中替米沙坦葡萄糖醛酸化的主要参与酶。
结论
正如最近报道的那样（Riedmaier 等人，Clin Pharmacol Ther 2010;87:65-73），UGT1A1*28 被认为增强了 UGT1A3 的蛋白表达，从而增加了替米沙坦的葡萄糖醛酸化活性，并降低了替米沙坦的血浆浓度。
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